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Therefore, we aimed to elucidate the effects of DPP-4 inhibitor and\/or SGLT2 inhibitor on \u03b2-cell mass and function and compared their effects between in an early and advanced phase of diabetes. We used 7-week-old <jats:italic>db\/db<\/jats:italic> mice as an early phase and 16-week-old mice as an advanced phase and treated them for 2\u00a0weeks with oral administration of linagliptin, empagliflozin, linagliptin\u2009+\u2009empagliflozin (L\u2009+\u2009E group), and 0.5% carboxymethylcellulose (Cont group). Blood glucose levels in Empa and L\u2009+\u2009E group were significantly lower than Cont group after treatment. In addition, \u03b2-cell mass in L\u2009+\u2009E group was significantly larger than Cont group only in an early phase, accompanied by increased Ki67-positive \u03b2-cell ratio. In isolated islets, mRNA expression levels of insulin and its transcription factors were all significantly higher only in L\u2009+\u2009E group in an early phase. Furthermore, mRNA expression levels related to \u03b2-cell differentiation and proliferation were significantly increased only in L\u2009+\u2009E group in an early phase. In conclusion, combination of DPP-4 inhibitor and SGLT2 inhibitor exerts more beneficial effects on \u03b2-cell mass and function, especially in an early phase of diabetes rather than an advanced phase.<\/jats:p>","DOI":"10.1038\/s41598-021-94896-w","type":"journal-article","created":{"date-parts":[[2021,8,9]],"date-time":"2021-08-09T10:10:36Z","timestamp":1628503836000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Early combination therapy of empagliflozin and linagliptin exerts beneficial effects on pancreatic \u03b2 cells in diabetic db\/db mice"],"prefix":"10.1038","volume":"11","author":[{"given":"Yoshiro","family":"Fushimi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Obata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junpei","family":"Sanada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Nogami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Ikeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Yamasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiyuki","family":"Obata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Shimoda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhei","family":"Nakanishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoatsu","family":"Mune","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Kaku","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Kaneto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,9]]},"reference":[{"key":"94896_CR1","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/S0092-8674(00)80709-6","volume":"97","author":"SI Taylor","year":"1999","unstructured":"Taylor, S. 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H.K. has received honoraria for lectures, received scholarship grants, and received research grant from Novo Nordisk Pharma, Sanofi, Eli Lilly, Boehringer Ingelheim, Taisho Pharma, Sumitomo Dainippon Pharma, Takeda Pharma, Ono Pharma, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Kissei Pharma, MSD, AstraZeneca, Astellas, Novartis, Kowa. The rest authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"16120"}}